Eltrombopag chemically known as (Z)-3′-(2-(1-(3, 4-dimethylphenyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)hydrazinyl)-2′-hydroxybiphenyl-3-carboxylic acid having the following chemical compound of formula I:

Eltrombopag is marketed as bis-(monoethanolmine) or Olamine salt under the trade name PROMACTA® by GlaxoSmithKline, which is shown as formula II:

Eltrombopag bis-(monoethanolmine) is useful as an agonist of thrombopoietin (TPO) mimetic receptor, particularly in the treatment of thrombocytopenia. Eltrombopag interacts with the transmembrane domain of the TPO receptor (also known as cMp1) leading to increased platelet production.
U.S. Pat. No. 7,160,870 (the U.S. '870 patent) discloses Eltrombopag and its salts. U.S. Pat. No. 7,547,719 discloses, bisethanolamine salt of Eltrombopag, which is also known as olamine salt of Eltrombopag. U.S. '870 to patent discloses a process for the preparation of Eltrombopag free acid, which is shown schematically by Scheme I:

U.S. Pat. No. 7,956,048 B2 discloses different crystalline forms of Eltrombopag free acid as well as process for the preparation of crystalline forms. U.S. '048 patent also discloses characterization of crystalline forms (PXRD & 13C NMR). Different process for the preparation of crystalline forms and their characterization has been described below:
13C NMRCrystalline form and its Process2θ (±0.2)(±0.2 ppm)Anhydrous Form I:4.0, 7.3, 7.7, 12.1166.9,A mixture of Eltrombopag Form I and Form IIIand 16.1155.4,(500 mg) was suspended in acetone (30 mL) and141.4,heated to 57° C. Water (10 mL) was added and the134.1,resulting suspension was left to cool to reach a130.4,temperature of 22° C. The precipitate was filtered125.7, 119.8and dried for 1 h at 50° C./5 mbar to yield 314 mg.and 117.8OrEltrombopag Form III (96 mg) was dissolved in 10 mLof glacial acetic acid (99.5%) while heating toboiling point of glacial acetic acid (118° C.). The hotsolution was then filtered and left to crystallizewhile cooling to room temperature (23° C.). Theobtained product was collected by filtration anddried at 35° C., under vacuum. 40 mg of brightorange product was obtained.OrA mixture of Eltrombopag Form I and Form III,(230 mg) was dissolved in 25 mL of glacial aceticacid (99.5%) while heating. The hot solution wasthen filtered and left to crystallize while cooling inan ice bath. The obtained product was collected byfiltration and dried at 35° C. under vacuum. 139 mgof bright orange product was obtained.OrEltrombopag Form III (24.42 g, HPLC purity: 98%)was suspended in 470 ml of glacial acetic acid(>99.5%) in a 1 L reactor. The suspension wasstirred for five hours under reflux, then cooled to40° C. and stirred for one hour at the sametemperature. Crystals formed and were filtrated off,washed with 100 mL of methanol:water (1:1) anddried at 60° C./0 mbar for twelve hours yielding20.49 g orange solid of Eltrombopag form I (Yield =88%; HPLC purity: 99.94%).OrCrude Eltrombopag (151 g, HPLC purity: 98.5%)was suspended in 2.9 L of glacial acetic acid in 3 Lreactor. The suspension was stirred for five hoursunder reflux and cooled to 40° C. Crystals formedand were filtrated off, washed with 200 mL ofmethanol:water (1:1) and dried at 60° C./0 mbarovernight yielding 133 g orange solid of pureEltrombopag free acid (HPLC: 99.8%; XRPD:Form I).Form III:9.2, 11.2, 12.2170.6,Eltrombopag (210 mg) was dissolved in 15 mL ofand 14.0128.7, 124.2ethyl acetate while heating at reflux (77° C.). The hotand 113.8solution was then filtered and left to crystallizewhile cooling in an ice bath (0-5° C.). The obtainedproduct was collected by filtration and driedovernight at 22° C. 82 mg of bright orange productwas obtained.Form IV:8.4, 11.0, 13.1,—Eltrombopag (500 mg) Form I was suspended in21.1 and 22.0Methanol/water mixture 1:3 (40 mL) and heated to80° C. The suspension was left to cool to 22° C. Theprecipitate was filtered, washed with Methanol andair dried on air over night to yield 321 mg.Form V:5.3, 9.2, 14.0171.9,A mixture of Eltrombopag Form I and Form III155.4,(500 mg) was dissolved in tetrahydrofuran (10 mL)136.3, 121.3and mixture of water/Methanol (1:1, 10 mL) wasadded dropwise. The precipitate was filtered anddried for 2 h at 50° C./5 mbar to yield 340 mg.OrA mixture of Eltrombopag Form I and Form III(500 mg) was dissolved in tetrahydrofuran (10 mL)and water (10 mL) was added dropwise. Thesolution was stirred 1 hour during which aprecipitate was formed. The precipitate was filtered,washed with tetrahydrofuran/water (1:1, 10 mL)and dried for 2 h at 50° C./5 mbar to yield 423 mg.OrEltrombopag Form VIII (1.092 g) was dissolved in6.4 mL of tetrahydrofuran while heating at 60° C.When a clear solution was obtained, 6.4 ml of waterwas added and reaction mixture was stirred for 1hour at 22° C. A solid precipitated and was filtered,washed with water, and dried at 50° C. undervacuum, 1 hour. 1.023 g of bright orange productwas obtained.OrEltrombopag (8.65 g) was dissolved intetrahydrofuran (50 mL) with heating to reflux.Water (50 mL) was added dropwise and the solutionwas stirred for 1 hour at 22° C. during which aprecipitate was formed. The precipitate was filtered,washed with water and dried for 2 h at 50° C./5 mbarto yield 7.70 g.Form VI:5.9, 8.4, 8.8, 10.3,—Eltrombopag Form V (2 mg) was placed in11.7, 14.7, 16.2,aluminum sample pan with a small hole on lid under23.5 and 24.8nitrogen pouring at a flow rate of 35 ml/min. Thesample was equilibrated at 20° C., heated withheating rate of 10° C. per minute up to 120° C.Form VII:7.3, 12.5, 18.8,—Eltrombopag Form V (2 mg) was placed in22.5 and 26.0aluminum sample pan with a small hole on lid undernitrogen pouring at a flow rate of 35 ml/min. Thesample was equilibrated at 20° C., heated withheating rate of 10° C. per minute up to 213° C. TheDSC was calibrated with indium. The sample wascooled at a rate of 10° C./min up to 20° C.Form VIII:5.3, 11.0, 17.0,—Eltrombopag Form IV (500 mg) was suspended in19.1 and 28.2dichloromethane (10 mL) and water (5 mL). Thesuspension was basified with sodium hydroxide, 1M(2.5 mL) and then acidified with hydrochloric acid,1M (2.5 mL). The solid was filtered off and dried ina vacuum oven for 1/2 h on 50° C./5 mbarForm IX:8.8, 10.9, 13.4—Eltrombopag Form I (15-20 mg) was dissolved inand 26.7tetrahydrofuran (2 mL) with heating and left at22° C.Form X:8.2, 13.2, 16.3—Eltrombopag Form I (15-20 mg) was dissolved inand 25.3dimethylsulfoxide (2 mL) with heating and left at22° C.Form XI:4.1, 8.1, 12.1 and—Eltrombopag Form I (15-20 mg) was dissolved in16.2acetone (6 mL) with heating, filtered and left at22° C.Form XII:4.6, 7.6, 8.9, 10.4,—Eltrombopag form I (15-20 mg) was dissolved in13.3, 14.1, 15.1,methoxybenzene (anisole) (6 mL) with heating.16.2 and 23.9Solution was left at 22° C.Form XIII3.9, 7.8, 11.7,—Eltrombopag Form I (15-20 mg) was dissolved in12.4, 15.5, 20.5,diethyl ether (6 mL), with heating, filtered and left23.0 and 25.0at 22° C.Form XIV:4.0, 5.0, 7.9, 9.1,—Eltrombopag Form I (15-20 mg) was dissolved in10.7, 15.1, 19.0ethyl acetate (6 Ml) with heating, filtered and left atand 21.422° C. Obtained crystals were analyzed by powderXRD.Form XV:4.0, 8.1, 9.4, 11.5—Eltrombopag Form X (2 mg )was placed in a DSC12.0, 16.2, 12.5,and was heated to a temperature of 160° C., under N220.9 and 27.8Form XVI:5.9, 7.1, 9.5, 11.2,168.7,Crystalline 3′-amino-2′-hydroxybiphenyl-3-carboxylic13.9, 15.4, 17.4,156.7,acid Form II (50 g, 218 mmol, PXRD pattern at21.2, 25.5 and127.6, 112.8FIG. 34) (Supplier: Topharman Shangai Co., Ltd;26.2Batch No: BPCA: 090921BPCA) was added to asolvent mixture of methanol (1 L) and hydrochloricacid; 4M (137 mL) in a 1 L reactor with stirring atroom temperature (cca 22° C.). The resultingsolution was stirred for 1A h and then cooled to 0-5° C.A refrigerated solution of sodium nitrite (15 g,217 mmol) in water (50 mL) was added to thereaction mixture over 20 min (maintaining thereaction temperature below 10° C.) and the stirringwas continued for 1 h. A Solution of sulfamic acid(2.22 g, 23 mmol) in water (50 mL) was added tothe reaction mixture and stirred for 1 h at 5° C. Theresulting reaction mixture was heated to roomtemperature and triethylamine (cca 80 mL) wasadded to adjust to pH 7-8. Crystalline 1-(3,4-dimethylphenyl)-3-methyl-1H-pyrazol-5-ol(“pyrazole”) form II (44 g, 218 mmol, PXRDpattern at FIG. 33) (Supplier: Topharman ShangaiCo., Ltd; Batch No: 090805PYRAZOL) was addedin one portion to the reaction mixture and stirred for2 h at room temperature, maintaining the pH 7-8.Hydrochloric acid (4M, cca 40 mL) was added toadjust the pH to 8 over 20 minutes with stirring. Theprecipitated solid was filtered, washed and dried at40° C./5 bar for about 18 h to yield 100 g (90%) ofEBP as a bright orange powder
U.S. Pat. No. 7,956,048 B2 also discloses Eltrombopag olamine crystalline forms, its process for preparation and designated as Form I, Form II and Form III. Further, this patent also discloses Eltrombopag olamine amorphous form and its process for preparation.
However, prior-art Eltrombopag free acid crystalline forms reported above are not pure crystalline form and contain some amount of amorphous form, and hence not stable. The present inventors have found that the acetic acid used during the preparation leads to unpure crystalline forms, which are not stable. In view of this present inventors have avoided acetic acid and found a crystalline form of Eltrombopag free acid, which is stable, reproducible and free of other polymorphic forms.